The present invention is directed to a new process for the synthesis of vinyl sulfoxides, in particular diarylvinyl sulfoxides. These compounds are useful for the synthesis of benzo[b]thiophenes.
Benzo[b]thiophenes have been prepared by a number of different synthetic routes. One of the most widely used methods is the oxidative cyclization of o-mercaptocinnamic acids. This route is limited to the preparation of benzo[b]-thiophene-2-carboxylates. 2-Phenylbenzo[b]thiophenes are prepared by acid-catalyzed cyclization of 2-phenylthioacetal-dehyde dialkyl acetals. Unsubstituted benzo[b]thiophenes are prepared by catalytic condensation of styrene and sulfur. 3-Substituted benzo[b]thiophenes are prepared by acid-catalyzed cyclization of arylthiomethyl ketones; however, this route is limited to the preparation of 3-alkylbenzo[b]thiophenes. See Campaigne, xe2x80x9cThiophenes and their Benzo Derivatives: (iii) Synthesis and Applications,xe2x80x9d in Comprehensive Heterocyclic Chemistry (Katritzky and Rees, eds.), Volume IV, Part III, 863-934 (1984). 3-Chloro-2-phenylbenzo[b]thiophene is prepared by the reaction of diphenylacetylene with sulfur dichloride. Barton and Zika, J. Org. Chem., 35, 1729-1733 (1970). Benzo[b]thiophenes have also been prepared by pyrolysis of styryl sulfoxides. However, low yields and extremely high temperatures make this route unsuitable for production-scale syntheses. See Ando, J. Chem. Soc., Chem. Comm., 704-705 (1975).
The preparation of 6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophenes was described in U.S. Pat. Nos. 4,133,814 and 4,380,635. One process described in these patents is the acid-catalyzed intramolecular cyclization/rearrangement of xcex1-(3-methoxyphenylthio)-4-methoxyacetophenone. The reaction of this starting compound in neat polyphosphoric acid at about 85xc2x0 C. to about 90xc2x0 C. gives an approximate 3:1 mixture of two regioisomeric products: 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 4-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene. These isomeric benzo[b]thiophenes co-precipitate from the reaction mixture, producing a mixture containing both compounds. To obtain a single regioisomer, the regioisomers must be separated, such as by chromatography or fractional crystallization. Therefore, there currently exists a need for an efficient and regiospecific synthesis of 2-arylbenzo[b]thiophenes from readily available starting materials. The products of the present invention are useful for the efficient and regiospecific synthesis of 2-arylbenzo[b]thiophenes from readily available starting materials.
The present invention is directed to a new process for the synthesis of vinyl sulfoxides, in particular diarylvinyl sulfoxides. Specifically, the present invention is directed to a process for preparing a compound of the formula 
wherein:
R1 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, or amino;
R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, or amino; and
R3 is a thermally-labile or acid-labile C2-C10 alkyl, C4-C10 alkenyl, or aryl(C1-C10 alkyl) group having a tertiary carbon atom adjacent to the sulfur atom;
comprising the steps of:
(1) oxidizing a benzyl sulfide of the formula: 
xe2x80x83wherein R2 and R3 are as defined above; with an oxidizing agent to produce a benzyl sulfoxide of the formula: 
xe2x80x83wherein R2 and R3 are as defined above;
(2) reacting said benzyl sulfoxide with a strong base to form a benzylic anion;
(3) condensing said benzylic anion with a benzaldehyde of the formula 
xe2x80x83wherein R1 is as defined above;
(4) reacting the condensation product from step 3 with an acid chloride to produce an ester of the formula 
wherein:
R1, R2, and R3 are as defined above; and
R4 is CO(C1-C6 alkyl), CO(aryl), CO(arylalkyl), SO2(C1-C6 alkyl), SO2(aryl), SO2 (aryalkyl) CO2(C1-C6 alkyl) CO2(aryl), CO2(arylalkyl), or CON(C1-C6 alkyl)2; and
(5) treating said ester with a second strong base. The E and Z regioisomers the formula II compounds are represented by the following structures: 
Another aspect of the present invention is a process for the regioselective synthesis of the Z isomer of the formula II compounds. In particular, the present invention relates to a process for preparing a compound of the formula 
wherein:
R1 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, or amino;
R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, or amino; and
R3 is a thermally-labile or acid-labile C2-C10 alkyl, C4-C10 alkenyl, or aryl(C1-C10 alkyl) group having a tertiary carbon atom adjacent to the sulfur atom;
comprising the steps of:
(1) reacting a benzyl sulfide of the formula: 
xe2x80x83wherein R2 and R3 are as defined above; with a strong base to form a benzylic anion;
(2) condensing said benzylic anion with a benzaldehyde of the formula 
xe2x80x83wherein R1 is as defined above;
(3) reacting the condensation product from step 2 with an acid chloride to produce an ester of the formula 
wherein:
R1, R2, and R3 are as defined above; and
R4 is CO(C1-C6 alkyl), CO(aryl), CO(arylalkyl), SO2(C1-C6 alkyl), SO2(aryl), SO2(arylalkyl), CO2(C1-C6 alkyl), CO2(aryl), CO2(arylalkyl), or CON(C1-C6 alkyl)2;
(4) treating said ester with a second strong base to produce a styryl sulfide of the formula 
xe2x80x83wherein R1, R2, and R3 are as defined above; and
(5) oxidizing said styryl sulfide with an oxidizing agent.
The term xe2x80x9cC1-C6 alkylxe2x80x9d represents a straight or branched alkyl chain having from one to six carbon atoms. Typical C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, 2-methylpentyl, and the like. The term xe2x80x9cC1-C4 alkylxe2x80x9d represents a straight or branched alkyl chain having from one to four carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, i-butyl, and t-butyl.
The term xe2x80x9cC1-C4 alkoxyxe2x80x9d represents groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and like groups. The term xe2x80x9chaloxe2x80x9d refers to fluoro, chloro, bromo, or iodo groups.
The term xe2x80x9carylxe2x80x9d represents groups such as phenyl and substituted phenyl. The term xe2x80x9csubstituted phenylxe2x80x9d represents a phenyl group substituted with one or more moieties chosen from the group consisting of halo, hydroxy, nitro, C1-C4 alkyl, C1-C4 alkoxy, trichloromethyl, and trifluoromethyl. Examples of a substituted phenyl group include 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-propylphenyl, 4-n-butylphenyl, 4-t-butylphenyl, 3-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl, 2-fluoro-5-methylphenyl, 2,4,6-trifluorophenyl, 2-trifluoro-methylphenyl, 2-chloro-5-trifluoromethylphenyl, 3,5-bis-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, 4-hydroxy-3-methylphenyl, 3,5-dimethyl, 4-hydroxyphenyl, 2-methyl-4-nitrophenyl, 4-methoxy-2-nitro-phenyl, and the like.
The term xe2x80x9carylalkylxe2x80x9d represents a C1-C4 alkyl group bearing one or more aryl groups. Representatives of this group include benzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl (such as p-chlorobenzyl, p-bromobenzyl, p-iodobenzyl), 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 2-methyl-2-phenylpropyl, (2,6-dichlorophenyl)methyl, bis(2,6-dichlorophenyl)methyl, (4-hydroxyphenyl)methyl, (2,4-dinitrophenyl)methyl, diphenylmethyl, triphenylmethyl, (p-methoxyphenyl)-diphenylmethyl, bis(p-methoxyphenyl)methyl, bis(2-nitrophenyl)methyl, and the like.
The term xe2x80x9carylalkoxylxe2x80x9d represents a C1-C4 alkoxy group bearing one or more aryl groups. Representatives of this group include benzyloxy, o-nitrobenzyloxy, p-nitrobenzyloxy, p-halobenzyloxy (such as p-chlorobenzyloxy, p-bromobenzyloxy, p-iodobenzyloxy), 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 2-methyl-2-phenylpropoxy, (2,6-dichlorophenyl)methoxy, bis(2,6-dichlorophenyl)methoxy, (4-hydroxyphenyl)methoxy, (2,4-dinitrophenyl)methoxy, diphenylmethoxy, triphenylmethoxy, (p-methoxyphenyl)-diphenylmethoxy, bis(p-methoxyphenyl)methoxy, bis(2-nitrophenyl)methoxy, and the like.
The term xe2x80x9cthermally-labile or acid-labile C2-C10 alkyl, C4-C10 alkenyl, or aryl(C1-C10 alkyl) groupxe2x80x9d represents a group that is readily removed from the sulfoxide (SO) group under heating or by treatment with the acid catalyst. The thermally-labile or acid-labile C2-C10 alkyl groups are straight or branched alkyl chains having from two to ten carbon atoms and having at least one beta-hydrogen atom. Representative thermally-labile or acid-labile C2-C10 alkyl groups include ethyl, n-propyl, i-propyl, 1,1-dimethylpropyl, n-butyl, sec-butyl, t-butyl, 1,1-dimethylbutyl, 2-methylbutyl, 3-methylbutyl, 1-methylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,4-dimethylbutyl, 3,3-dimethylbutyl, n-pentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-hexyl, and the like. The thermally-labile or acid-labile C4-C10 alkenyl groups are straight or branched alkenyl chains having from four to ten carbon atoms, at least one site of unsaturation, and either a beta-hydrogen or delta-hydrogen atom. Representative thermally-labile or acid-labile C4-C10 alkenyl groups include 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 2-methyl-3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and the like. The term thermally-labile or acid-labile aryl(C1-C10 alkyl) represents thermally-labile or acid-labile C2-C10 alkyl groups additionally containing one or more aryl groups and aryl-substituted methyl groups. Representative aryl(C1-C10 alkyl) groups include benzyl, diphenylmethyl, triphenylmethyl, p-methoxybenzyl, 2-phenylethyl, 2-phenyl-propyl, 3-phenyl-propyl, and the like. The term xe2x80x9cthermally-labile or acid-labile C2-C10 alkyl, C4-C10 alkenyl, or aryl(C1-C10 alkyl) group having a tertiary carbon atom adjacent to the sulfur atomxe2x80x9d includes, but is not limited to, such groups as t-butyl, 1,1-dimethylpropyl, 1,1-dimethylbutyl, 1-ethyl-1-methylpropyl, 1,1-dimethylpentyl, 1-ethyl-1-methylbutyl, 1,1-diethylpropyl, 1,1-dimethylhexyl, triphenylmethyl, and the like.
The term xe2x80x9cacid chloridexe2x80x9d includes acyl chlorides, such as acetyl chloride and benzoyl chloride; sulfonyl chlorides, such as methanesulfonyl chloride, benzenesulfonyl chloride, 1-butanesulfonyl chloride, ethanesulfonyl chloride, isopropylsulfonyl chloride, and p-toluenesulfonyl chloride; alkoxycarbonyl chlorides, such as methoxycarbonyl chloride and benzyloxycarbonyl chloride; and dialkylaminocarbonyl chlorides, such as N,N-dimethylaminocarbonyl chloride. Preferably the acid chloride is a sulfonyl chloride. More preferably, the acid chloride is methanesulfonyl chloride.
When R3 has a tertiary carbon adjacent to the sulfur atom, the Z regioisomer of the formula II compounds can be prepared selectively by a route as shown in Scheme 1. 
Generally, a benzyl alcohol, a formula V compound, is reacted with a mercaptan of the formula R3SH to produce a benzyl sulfide, a formula VI compound. This benzyl sulfide is reacted with a strong base, forming a benzylic anion, which is condensed with a benzaldehyde. This condensation product is reacted with an acid chloride and the resulting intermediate ester treated with a second strong base to produce a styryl sulfide, a formula IIIZ compound. This styryl sulfide is then oxidized with an oxidizing agent to produce the formula IIZ compound.
The first step in the synthesis of the Z styryl sulfoxide compounds is the conversion of a benzyl alcohol to a benzyl sulfide, formula VI compound. The reaction of the formula V compound, where R2 is as defined above, with a mercaptan of the formula R3SH, wherein R3 is a thermally-labile or acid-labile C2-C10 alkyl, C4-C10 alkenyl, or aryl(C1-C10 alkyl) group having a tertiary carbon atom adjacent to the sulfur atom, in the presence of a Lewis acid produces the benzyl sulfide, a formula VI compound. Suitable Lewis acids for this transformation are zinc bromide, zinc chloride, zinc iodide, ferric chloride, titanium(IV) chloride, aluminum trichloride, and aluminum tribromide, preferably zinc iodide. The reaction is generally carried out in an organic solvent, such as 1,2-dichloroethane or methylene chloride. When the reaction is carried out at room temperature, the reaction is complete after about 18 hours.
The benzyl sulfide is reacted with a strong base to form a benzylic anion. Suitable strong bases for this reaction include metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, and potassium t-butoxide; sodium hydride; and alkyllithiums, such as n-butyllithium, t-butyllithium, sec-butyllithium, and methyllithium. The preferred strong base for this reaction is n-butyllithium. The preferred solvent for this reaction is dry tetrahydrofuran. When n-butyllithium is used as the strong base, the reaction is carried out at a temperature of about xe2x88x9235xc2x0 C. to about xe2x88x9215xc2x0 C.
The benzylic anion is condensed with a benzaldehyde to prepare an intermediate condensation product. The benzaldehyde has the general formula R1(C6H4)CHO, wherein R1 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, or amino. Preferably, the benzylic anion is prepared and the condensation product is formed in situ by adding the benzaldehyde to the cold solution of the benzylic anion.
The condensation product is treated with an acid chloride to produce an intermediate ester. Representative acid chlorides include acyl chlorides, such as acetyl chloride and benzoyl chloride; sulfonyl chlorides, such as methanesulfonyl chloride, benzenesulfonyl chloride, 1-butanesulfonyl chloride, ethanesulfonyl chloride, isopropylsulfonyl chloride, and p-toluenesulfonyl chloride; alkoxycarbonyl chlorides, such as methoxycarbonyl chloride and benzyloxycarbonyl chloride; and dialkylaminocarbonyl chlorides, such as N,N-dimethylaminocarbonyl chloride; preferably a sulfonyl chloride. Preferably, methanesulfonyl chloride is added to the reaction mixture shortly after formation of the condensation product.
This intermediate ester is reacted with a second strong base to produce a styryl sulfide, a formula IIIZ compound where R1, R2, and R3 are as defined above. Suitable strong bases for this reaction include metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, and potassium t-butoxide; sodium hydride; alkyllithiums, such as n-butyllithium, t-butyllithium, sec-butyllithium, and methyllithium; and metal amides, such as sodium amide, magnesium diisopropylamide, and lithium diisopropylamide. The preferred strong base for this reaction is potassium t-butoxide. Generally, this reaction is carried out at about 15xc2x0 C. to about room temperature, preferably at room temperature.
The styryl sulfide is oxidized to prepare the corresponding styryl sulfoxide. Suitable oxidizing agents for this reaction are peracids, such as peracetic acid and m-chloroperoxybenzoic acid; organic peroxides, such as t-butyl peroxide; and hydrogen peroxide. Preferably the oxidizing agent is peracetic acid. This oxidation is typically carried out in an organic solvent, such as toluene, benzene, xylene, methanol, ethanol, methylacetate, ethylacetate, methylene chloride, 1,2-dichloroethane, or chloroform; preferably methylene chloride. This oxidation can be carried out at a temperature of about xe2x88x9240xc2x0 C. to about 0xc2x0 C.
Alternatively, when R3 has a tertiary carbon adjacent to the sulfur atom, the benzyl sulfide intermediate (formula VI compound) can be used to produce a mixture of E and Z isomers of the styryl sulfoxides, the formula II compounds. This synthesis is outlined is Scheme 2. 
The benzyl sulfide, prepared as described above, is oxidized to produce the corresponding benzyl sulfoxide. This benzyl sulfoxide is reacted with a strong base, and the resulting anion condensed with a benzaldehyde. The condensation product is reacted with an acid chloride and the resulting intermediate ester reacted with a second strong base to produce the styryl sulfoxide.
The benzyl sulfide, the formula VI compound, wherein R2 is as defined above and R3 is a thermally-labile or acid-labile C2-C10 alkyl, C4-C10 alkenyl, or aryl(C1-C10 alkyl) group having a tertiary carbon atom adjacent to the sulfur atom, is oxidized to produce the corresponding benzyl sulfoxide, formula X compound. Suitable oxidizing agents for this reaction are peracids, such as peracetic acid and m-chloroperoxybenzoic acid; organic peroxides, such as t-butyl peroxide; and hydrogen peroxide. Preferably the oxidizing agent is peracetic acid. This oxidation is typically carried out in an organic solvent, such as toluene, benzene, xylene, methanol, ethanol, methylacetate, ethylacetate, methylene chloride, 1,2-dichloroethane, or chloroform; preferably at a temperature of about xe2x88x9230xc2x0 C. to about 5xc2x0 C.
The benzyl sulfoxide, formula X compound wherein R2 and R3 are as defined above, is reacted with a strong base to produce a benzylic anion. Suitable strong bases for this reaction include metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, and potassium t-butoxide; sodium hydride; alkyllithiums, such as n-butyllithium, t-butyllithium, sec-butyllithium, and methyllithium; and metal amides, such as sodium amide, magnesium diisopropylamide, and lithium diisopropylamide. The preferred base for this transformation is n-butyllithium. This deprotonation reaction is carried out in a dry organic solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, at a temperature of about xe2x88x9225xc2x0 C.
The benzylic anion is condensed, without isolation, with a benzaldehyde compound of the formula p-R1(C6H4)CHO, wherein R1 is as defined above. Preferably, about one equivalent of the benzaldehyde is added to the cold solution prepared as described in the preceding paragraph. The resulting diastereomeric mixture of condensation products may be isolated, or preferably used in the next step without isolation.
The condensation product is optionally treated with a base, such as n-butyllithium, and reacted with an acid chloride. Representative acid chlorides include acyl chlorides, such as acetyl chloride and benzoyl chloride; sulfonyl chlorides, such as methanesulfonyl chloride, benzenesulfonyl chloride, 1-butanesulfonyl chloride, ethanesulfonyl chloride, isopropylsulfonyl chloride, and p-toluenesulfonyl chloride; alkoxycarbonyl chlorides, such as methoxycarbonyl chloride and benzyloxycarbonyl chloride; and dialkylaminocarbonyl chlorides, such as N,N-dimethylaminocarbonyl chloride; preferably a sulfonyl chloride. The acid chloride is added to the cold reaction mixture, then the resulting mixture is allowed to warm to room temperature. Preferably, methanesulfonyl chloride is added to the reaction mixture shortly after formation of the condensation product, which eliminates the need to add additional base.
The resulting intermediate ester is reacted with a second strong base to produce the E and Z styryl sulfoxides, formula II compounds where R1, R2, and R3 are as defined above. Representative second strong bases for this elimination reaction include metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, and potassium t-butoxide; sodium hydride; alkyllithiums, such as n-butyllithium, t-butyllithium, sec-butyllithium, and methyllithium; and metal amides, such as sodium amide, magnesium diisopropylamide, and lithium diisopropylamide. The preferred base for this transformation is potassium t-butoxide. Preferably, a 20% excess, such as 1.2 equivalents, of the second base are added. Generally, this reaction is carried out at a temperature of about 15xc2x0 C. to about room temperature, preferably at room temperature.
The intermediate styryl sulfoxides are useful for the synthesis of 2-arylbenzo[b]thiophenes as shown in Scheme 3. 
Generally, the intermediate styryl sulfoxide compounds are heated and treated with acid catalysts to produce the formula I compounds. Suitable acid catalysts for this reaction include Lewis acids or Brnsted acids. Representative Lewis acids include zinc chloride, zinc iodide, aluminum chloride, and aluminum bromide. Representative Brnsted acids include inorganic acids, such as sulfuric and phosphoric acids; carboxylic acids, such as acetic and trifluoroacetic acids; sulfonic acids, such as methanesulfonic, benzenesulfonic, 1-naphthalenesulfonic, 1-butanesulfonic, ethanesulfonic, 4-ethylbenzenesulfonic, 1-hexanesulfonic, 1,5-naphthalenedisulfonic, 1-octanesulfonic, camphorsulfonic, trifluoromethanesulfonic, and p-toluene-sulfonic acids; and polymeric arylsulfonic acids, such as Nafion(copyright), Amberlyst(copyright), or Amberlite(copyright). The more preferred acid catalysts are sulfonic acids, such as methanesulfonic acid, benezene-sulfonic acid, camphorsulfonic, and p-toluenesulfonic acid. The most preferred acid catalyst is p-toluenesulfonic acid. Typically, a solution of the acid catalyst in organic solvent, such as toluene, benzene, xylene, or a high-boiling halogenated hydrocarbon solvents, such as 1,1,2-trichloro-ethane, is heated to about 80xc2x0 to about 140xc2x0 C., and treated with a solution of the styryl sulfoxide in the same solvent. An excess amount of the acid catalyst is used, preferably two equivalents of the acid. For best results, the final concentration of the starting compound is about 0.01 M to about 0.2 M, preferably 0.05 M. Furthermore, best yields are obtained when the styryl sulfoxide is slowly added to the heated acid solution over a period of about 20 minutes to about three hours. For best results, residual water is removed from the reaction solution by the use of a Dean-Stark trap or Soxhlet extractor, and the reaction is purged with purified nitrogen.
The formula I compounds are useful as intermediates in the synthesis of a series of 3-aroyl-2-arylbenzo[b]-thiophenes. U.S. Pat. Nos. 4,133,814 and 4,418,068, which are incorporated herein by reference, described these 3-aroyl-2-arylbenzo[b]thiophenes, as well as methods for their preparation from the formula I compounds. An improved synthesis of a group of these 3-aroyl-2-arylbenzo[b]-thiophenes from the formula I compounds, wherein R1 and R2 are hydrogen, C1-C4 alkoxy, or arylalkoxy, is outlined in Scheme 4. 
The benzothiophene Formula I compound, wherein R1 and R2 are hydrogen, C1-C4 alkoxy, or arylalkoxy, is acylated with the formula XI compound, wherein R7 is chloro or hydroxy, in the presence of boron trichloride or boron tribromide; boron trichloride is preferred. The reaction can be carried out in a variety of organic solvents, such as chloroform, methylene chloride, 1,2-dichloroethane, 1,2,3-dichloropropane, 1,1,2,2-tetra-chloroethane, 1,2-dichlorobenzene, chlorobenzene, and fluorobenzene. The preferred solvent for this synthesis is 1,2-dichloroethane. The reaction is carried out at a temperature of about xe2x88x9210xc2x0 C. to about 25xc2x0 C., preferably at 0xc2x0 C. The reaction is best carried out at a concentration of the benzothiophene formula I compound of about 0.2 M to about 1.0 M. The acylation reaction is generally complete after about two hours to about eight hours.
When R1 and/or R2 is a C1-C4 alkoxy or arylalkoxy group, the acylated benzothiophene, is converted to a formula XI compound wherein R8 and/or R9 are hydroxy, without isolation of the product from the acylation reaction. This conversion is performed by adding additional boron trihalide or boron tribromide and heating the reaction mixture. Preferably, two to five molar equivalents of boron trihalide are added to the reaction mixture, most preferably three molar equivalents. This reaction is carried out at a temperature of about 25xc2x0 C. to about 40xc2x0 C., preferably at 35xc2x0 C. The reaction is generally complete after about 4 to 48 hours.
The acylation reaction or acylation/dealkylation reaction is quenched with an alcohol or a mixture of alcohols. Suitable alcohols for use in quenching the reaction include methanol, ethanol, and isopropanol. Preferably, the acylation/dealkylation reaction mixture is added to a 95:5 mixture of ethanol and methanol (3A ethanol). The 3A ethanol can be at room temperature or heated to reflux, preferably at reflux. When the quench is performed in this manner, the Formula XII compound conveniently crystallizes from the resulting alcoholic mixture. Generally, 1.25 mL to 3.75 mL of alcohol per millimole of the benzothiophene starting material are used.
The following examples further illustrate the present invention. The examples are not intended to be limiting to the scope of the invention in any respect, and should not be so construed. All experiments were run under positive pressure of dry nitrogen. All solvents and reagents were used as obtained. The percentages are generally calculated on a weight (w/w) basis; except for high performance liquid chromatography (HPLC) solvents which are calculated on a volume (v/v) basis. Proton nuclear magnetic resonance (1H NMR) spectra and 13C nuclear magnetic resonance spectra (13C NMR) were obtained on a Bruker AC-300 FTNMR spectrometer at 300.135 MHz or a GE QE-300 spectrometer at 300.15 MHz. Silica-gel flash chromatography was performed as described by Still et al. using Silica Gel 60 (230-400 mesh, E. Merck). Still et al., J. Org. Chem., 43, 2923 (1978). Elemental analyses for carbon, hydrogen, and nitrogen were determined on a Control Equipment Corporation 440 Elemental Analyzer. Elemental analyses for sulfur were determined on a Brinkman Colorimetric Elemental Analyzer. Melting points were determined in open glass capillaries on a Mel-Temp II melting point apparatus or a Mettler FP62 Automatic instrument, and are uncorrected. Field desorption mass spectra (FDMS) were obtained using. Varian Instruments VG 70-SE or VG ZAB-3F mass spectrometer. High resolution free atom bombardment mass spectra (FABMS) were obtained using a Varian Instruments pectrometer.
The in situ yields of 6-methoxy-2-(4-methoxyphenyl) benzo[b]thiophene were determined by high performance liquid chromatography (HPLC) in comparison to an authentic sample of this compound prepared by published synthetic routes. See U.S. Pat. No. 4,133,814. Generally, samples of the reaction mixture was diluted with acetonitrile and the diluted sample assayed by HPLC using a Zorbax RX-C8 column (4.6 mmxc3x9725 cm) with UV detection (280 nm). The following linear gradient solvent system was used for this analysis:
The amount (percentages) of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]thiophene hydrochloride in the crystalline material (potency) was determined by the following method. A sample of the crystalline solid (5 mg) was weighed into a 100-mL volumetric flask, and dissolved in a 70/30 (v/v) mixture of 75 nM potassium phosphate buffer (pH 2.0) and acetonitrile. An aliquot of this solution (10 xcexcL) was assayed by high performance liquid chromatography, using a Zorbax Rx-C8 column (25 cmxc3x974.6 mm ID, 5 xcexc particle) and UV detection (280 nm). The following gradient solvent system was used:
The percentage of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride in the sample was calculated using the peak area, slope (m), and intercept (b) of the calibration curve with the following equation:       %    ⁢          xe2x80x83        ⁢    potency    =                              peak          ⁢                      xe2x80x83                    ⁢          area                -        b            m        xc3x97                  sample        ⁢                  xe2x80x83                ⁢        volume        ⁢                  xe2x80x83                ⁢                  (          mL          )                            sample        ⁢                  xe2x80x83                ⁢        weight        ⁢                  xe2x80x83                ⁢                  (          mg          )                    
The amount (percentage) of solvent, such as 1,2-dichloroethane, present in the crystalline material was determined by gas chromatography. A sample of the crystalline solid (50 mg) was weighed into a 10-mL volumetric flask, and dissolved in a solution of 2-butanol (0.025 mg/mL) in dimethylsulfoxide. A sample of this solution was analyzed on a gas chromatograph using a DB Wax column (30 mxc3x970.53 mm ID, 1 xcexc particle), with a column flow of 10 mL/min and flame ionization detection. The column temperature was heated from 35xc2x0 C. to 230xc2x0 C. over a 12 minute period. The amount of solvent was determined by comparison to the internal standard (2-butanol).